Evaluation
of the Risk of Pathologic Fractures Secondary to Metastatic Bone Disease

Pathologic
fractures create a serious morbidity in patients with metastatic bone
disease. Orthopedic surgeons who treat patients with metastatic skeletal
lesions should focus on proactive treatments designed to prevent pathologic
fractures before they occur. Prevention of pathologic fractures result
in better patient outcome, lower cost, and less difficult operative procedures.
For this reason, it is critical to identify both patients and skeletal
lesions that are at increased risk of pathologic fracture. The goal of
this review is to establish a systematic screening tool and treatment
algorithm that orthopedic surgeons can easily apply to their patients
in order to optimize the management of metastatic skeletal disease.

Unlike fractures of normal bone, pathologic fractures occur during normal
activity or minor trauma due to weakening of the bone by disease. Conditions
associated with pathologic fractures include underlying metabolic disorders,
primary benign tumors, and primary and metastatic malignant tumors (q)
. The most common condition associated with pathologic fractures is osteoporosis(q).
This review will focus on the evaluation of fractures that occur secondary
to bone destruction by metastatic cancer. Prevention of pathologic fractures
is superior to treatment after the fact. Some of the advantages that have
been cited include shorter hospital stays(R,A); easier rehabilitation
and nursing with more rapid restoration of function (U,V,K,R); easier
radiotherapy treatment (R,A.); more immediate pain relief (U,V,K,R,A);
and faster and less complicated surgery (R,A).

In
order to determine which patients require prophylactic fixation to prevent
pathologic fracture, it is necessary to perform an accurate and reliable
risk evaluation. Many different characteristics have been proposed as
important criteria for determining risk of fracture. These include type
of cancer; type of treatment; size of the lesion; location of the lesion;
whether the lesion is lytic or blastic; and symptoms due to the lesion.
In addition, some have proposed a detailed biomechanical analysis based
on finite element modeling. the use of biomechanics to predict fracture.
This article will critically review the literature and provide guidelines
for estimating fracture risk that are useful for orthopedic surgeons.

PATIENT
FACTORS

Cancer
Diagnosis The patient's underlying cancer diagnosis is an important
component of their pathologic risk profile (Table 1). Breast cancer is
the most important source of bone metastasis, and it is responsible for
the majority of the skeletal metastases that require orthopedic consultation
(M). The risk of pathologic fracture increases with the duration of metastatic
disease. Because breast carcinoma has a relatively long survival, these
patients are more likely to sustain a pathological fracture. Based on
the author's experience, breast cancer metastases that are purely lytic
are more likely to fracture than those that are blastic or mixed lytic
and blastic. However, blastic lesions in high risk areas such as the proximal
femur have a high rate of fracture.

Prostate
cancer, combined with breast cancer, contributes to 80% of all skeletal
metastasis (O). Prostate cancer normally forms blastic metastases which
are less susceptible to fracture, but blastic lesions have been shown
to decrease the longitudinal stiffness of bone (?). In addition, some
of the treatments that are commonly given for prostate cancer increase
the likelihood of pathologic fracture. These include LHRH agonists, orchiectomy,
and radiation. In one study, patients receiving LHRH agnosists had a 9%
incidence of fracture, a rate significantly higher than similar patients
not receiving LHRH agonists (Cancer 1997, February 1st, Volume 79 (3),
Pg 545). Patients with prostate cancer who have had radiation to bony
areas, or who have low bone density due to hormone modification therapies
should be considered at increased risk for fracture.

Lung
cancer has a relatively aggressive course and a short survival after bone
metastasis. Thus fewer patients survive long enough to develop pathologic
fracture. Metastases are typically lytic and have a correspondingly higher
risk of fracture. A small proportion of lung cancer metastasis can occur
in bones below the elbow and the knee (acrometastasis). These lesions
are frequently painful and require radiation or surgical treatment due
to the pain rather than for risk of fracture as the risk of functionally
disabling fracture through an acrometastasis is low.

Bone
metastasis is diagnosed in 4% - 13% of patients with thyroid cancer (Marcocci
et al, Surgery 106:960-966, 1989 and McCormack, Cancer 19:181-184 1965.)
The lesions are frequently lytic and their fracture risk depends on their
location. Because patients with thyroid cancer may have prolonged survival
they are also at increased overall risk of pathological fracture. Approximately
25-50% of renal cell carcinomas metastasize to bone (r,s).

Renal
cell metastases to bone can be unusually expansile and destructive, which
creates an increased risk of pathologic fracture. Orthopedic surgeons
treating metastatic cancers should note that certain selected patients
with renal cell metastases may be candidates for aggressive surgical resection
for cure (?). Table 1: Origin and Rates of Metastasis to Skeleton Irradiation
of Lesion

Irradiation
of metastatic bone lesions also appears to increase the risk of pathologic
fracture (C, N, 1, G, R, K,A,Z). Keene et al found that 18% of patients
who underwent irradiation for metastatic breast carcinoma developed fractures.
Other authors have reported much higher incidences ranging from 26%-41%
(1,N,Z). Harrington (G) theorizes that radiotherapy increases the risk
for fracture because it causes temporary softening of the bone at the
tumor site. Radiation may lead to increased fracture risk due failure
of reossification after treatment. Beals and Snell reported that only
4% of lesions reossified after treatment (A). However, other authors have
found a 65%-85% incidence of reossification under similar circumstances,
assuming a fracture has not occurred (4, Q).

Pain Pain is an important but controversial criteria for evaluation
of pathologic fractures. In metastatic disease, pain may arise from enlargement
of the tumor, perilesional edema, increased intraosseous pressure, or
weakness from bone loss (1,X). The direct pressure exerted by the tumor
on the bone has been shown to stimulate the release of various pain mediators
including porstaglandins, bradykinins, and histamine (o). In addition,
tumor invasion of bone can lead to activation of mechanoreceptor and nociceptors
which leads to the development of pain (o). The controversy lies in whether
or not pain can be used as a sign of impending fracture. Fidler (B) stated
that pain could not be considered a reliable sign of an impending fracture
because only half of the patients in his study complained of pain. Keene
et al (C) found that most patients with metastatic bone cancer did develop
bone pain, but only 11% of them actually had fractures; therefore, he
concluded that pain was not an accurate indication of impending fracture.

Many
authors (A,D,E,F,G, R,1) feel that pain is an important indication for
prophylactic fixation. Some have singled out persistent pain despite radiation
(D,E,G) as a criterion for fixation while others state that pain caused
only by lytic lesions should undergo prophylactic fixation (F). In some
series, patients without pain had a low risk of fracture ( R) and patients
with functional pain had a high risk of fracture approaching 100% (R,
1). These finding suggest that pain may be a valuable sign of decreased
mechanical strength of bone and increased fracture risk (1).

LESION FACTORS

Relationship
of Lesion Size to Fracture Risk Beals and Snell (A) published highly
influential works in 1956 and 1961. Their work dealt only with patients
with breast cancer and only with lesions in the femur. Of the 19 fractures
that occurred in their first series, they found that 58% of these fractures
were predictable using the following criteria: Presence of a metastatic
lesion 2.5 cm in size or larger involving the femoral cortex or presence
of a defect of the same size in any location that caused pain to the patient.
These criteria were used in a second series and patients at risk for fracture
underwent prophylactic fixation of the diseased bone. This treatment reduced
the incidence of fracture from 32% to 9%.

Parrish
and Murray (J,E) used these criteria as indications for prophylactic fixation
when performing their studies on treatments of pathologic fractures. They
found that using these criteria led to decreased fractures and improved
the quality of life of their patients. In 1973, Fidler(B) retrospectively
studied 19 patients with pathologic fractures of the femur. He found that
100% of patients with greater than 50% cortical involvement developed
a fracture. Based on this data, he recommended that patients with involvement
of over half of the cortex should undergo surgery to stabilize the bone.
In 1981, Fidler (D) published another retrospective study of 66 patients
with 100 metastases in the long bones. His results corroborated his previously
reported indications for prophylactic fixation. He found that when greater
than 75% of the cortex is destroyed the incidence of fracture is 80%.
When less than 50% of the cortex is involved, the incidence is only 2.3%.

Zickel
and Mourandian(P) studied 34 patients with lesions in the proximal femur.
They concluded that involvement of even small parts of the cortex in the
subtrochanteric region places the femur at high risk for fracture and
warrants prophylactic fixation. According to their results, size of the
lesion did not correlate with risk of fracture. Keene et al supported
this conclusion as he found that all the measureable lesions that fractured
had a similar extent of cortical involvement as those that did not fracture
( C).In
1982, Harrington (4) recommended intramedullary nail fixation when there
is greater than 70% destruction of the cortex (G).

In
1989, Mirels (1) developed a scoring system to quantify the risk of pathologic
fracture based on a retrospective study of 78 irradiated metastatic bone
lesions. Unlike all the previous studies, Mirels combined four different
features of bone lesions in an attempt to create a more reliable risk
assessment (See Table 3).

His
system assigned points to the following four variables: the location of
the lesion (upper limb, lower limb, peritrochanter); the degree of pain
caused by the lesion (mild, moderate, severe); the type of lesion (lytic,
blastic, mixed); and the size of the lesion (<1/3, 1/3-2/3, >1/3). Adding
the points from each category determines the score. His data indicated
that a score of less than or equal to 7 out of 12 is indicative of a lesion
not at risk for fracture. A score of 8 out of 12 is associated with a
15% risk for fracture. The risk of fracture is 33% in patients with a
score of 9. Mirels concluded that a score of 9 or greater should be used
as an indication for prophylactic fixation. Mirels found that the combined
score was a more accurate predictor of fracture than any of the four factors
used separately. Pain and lesion size were more accurate predictors than
type of lesion or site of lesion. Confirming Fidler's conclusions, Mirels
found that the rate of fracture was only 5% when the lesion was less than
two thirds of the diameter of the bone, but increased to 81% when the
lesion was greater than two thirds of the diameter of the bone.

Accuracy
of Lesion Size Measurement Several authors have demonstrated the limitations
of using size-based criteria alone. In 1986, Keene et al (C) performed
a retrospective study of 203 female patients with 516 metastatic breast
cancer lesions that were located in the proximal femur. They showed that
57% of the metastases could not be accurately measured from plain radiograph
because they lacked a clear border between the lesion and normal bone.
Size-based criteria may not be applicable to bony lesions where the cortex
cannot be effectively measured, such as the spine, ribs, and pelvis (N).

Hipp
et al also stated that characteristics of both metastatic bone lesions
and physician observers lead to a very high degree of error and variability
in the measurement of lesions (5). Two physicians reading the same radiograph
and applying the same criteria might come to very different conclusions
about the need for prophylactic fixation, with potentially disastrous
consequences for the patient. In fact, Hipp et al found that experienced
orthopedic oncology surgeons could not consistently predict strength reductions
or load bearing capacity from radiographs or CT films (5). Therefore,
another method needs to be found to determine factor of risk that would
be easier for orthopedic surgeons to use.

Relationship
of Lesion Location to Fracture Risk Of the long bones in the peripheral
skeleton, the femur is the most common site for metastases followed by
the humerus (R,U). According to Knutson et al, 88.4% of all long bone
metastasis secondary to breast cancer involved the femur (R). Within the
long bones, the proximal part is most likely to be affected, especially
the peritrochanteric region of the femur (1, U,d). While metastases to
the long bones account for less than 20% of all fractures (O), Harrington
found that over half of these pathologic long bone fractures occurred
in the proximal femur (G). Some authors have suggested that the femur
is more likely to sustain a pathologic fracture than other long bones
(A,R,T,U,V). Dijkstra et al states that 25% of all long bone metastases
fracture, but the proximal femur has an incidence of 40-60% (U).

However,
Fidler (D) found no difference between the rate of fracture in upper limb
lesions versus lower limb lesions. Mirels also found that the peritrochanteric
region, while the most common area of the femur to develop metastases,
is not any more likely to fracture than other sites (1). Taking into consideration
the conflicting information in the literature, it is the authors opinion
that the orthopedic surgeon treating metastatic skeletal lesions should
have a relatively low threshold for prophylactic fixation of proximal
femur lesions. Any lesion between the lesser trochanter and the
femoral head causing functional pain or larger than 2.5 cm should be fixed
prophylactically. Pathologic fractures in this location produce
serious morbidity. The operative procedures applicable to the proximal
femur are familiar to all practicing orthopedic surgeons. The benefit
of prophylactic fixation significantly outweigh the risks of surgery.

Lytic
vs. Blastic Lesions While bone formation and destruction occur simulataneously
in most metastatic cancers, usually one predominates over the other. Mirels
(B) and others (4,f,P,N) have found that lytic lesions did have a higher
risk for fracture. Mirels found in his study that none of the blastic
lesions fractured, but 32% of the mixed lesions and 48% of the lytic lesions
did. He theorized that lytic lesions were a result of a more advanced
process of bone resorption . On the other hand, Hipp et al (g) found that
even though blastic lesions do increase bone density, they do not change
bone strength and they decrease the stiffness. Lytic lesions decrease
both strength and stiffness of the bone.

Biomechanical
Modeling of Fracture Risk Biochemical testing and computer modeling have
contributed to the understanding of fracture risk. Hipp et al (5) discusses
in vitro experimentation as an alternative to using clinical and radiographical
data to predict pathologic fractures. Studies have shown that even small
cortical defects can significantly reduce the strength of the bone (h,j,m).
Brooks et al found that drill holes as small as 2.8 mm or 3.6 mm in the
femoral mid-shaft significantly weakened the bone because of increases
in local stresses by the defect (h). Hipp found that a hole that reduced
the cross-sectional area of the bone by less than 40% reduced the torsional
strength of the bone by 70%. These results suggest that the 50% loss originally
stated by Fidler (B) as the cutoff for prophylactic fixation may be an
underestimation. Hipp et al (l) also found that the location and shape
of endosteal defects affected the degree of strength reduction in the
bone which would therefore affect the risk of fracture. If a defect causing
a 50% loss in cross sectional area is in the center of the femoral diaphysis,
the strength of the bone is reduced by 60%. However, if an identical defect
is located such that the thinnest wall was at the point of maximal bending
stress, the strength reduction was greater than 90%.

In
bones subjected to bending, it is the location of the defect that is important
in determining the amount of strength reduction. The length of the defect
along the long axis of the bone has a large effect on torsional strength.
A long defect with the same decrease in cross sectional area as a small
defect will cause a greater reduction in strength than the smaller defect.
The length of the defect does not significantly affect bone strength if
bones are subjected to bending (5,l). Studies need to be conducted that
study the effect of combinations of torsion and bending to determine how
they affect the strength of the bone. Biomechanics and computer models
promise to improve the accuracy of fracture risk prediction, but these
methods are not yet available for everyday use.

Summary
In summary, an orthopedic surgeon calculating risk of pathologic fracture
is likely to focus most of his or her attention on the appearance of lesion
of plain radiographs. The authors recommend that the size of the lesion
be considered in the context of the other factors that are mentioned by
Mirels et al (1). When the boundaries, or dimensions, of a lesion are
uncertain, the threshold for orthopedic stabilization should be lowered.

In
certain locations such as the femoral neck, the peritrochanteric region
of the femur, and the junction between the humeral head and the humeral
metaphysis, the risk and disability from pathologic fracture are so great
that orthopedic stabilization should be used in virtually all cases. Only
very small, well-delineated lesions in these high-risk locations should
be treated non-operatively. If the surgeon chooses non-operative care
for a small lesion in a high risk location, careful follow-up is required
since the lesions may progress to fracture before the treatment is completed.

RECOMMENDATIONS

There
is no doubt about the importance of determining which cancer patients
with metastatic bone disease have had enough damage to their bones to
increase their risk of developing a fracture. Prophylactic fixation of
these patients clearly decreases morbidity in patients compared to fixation
of completed fractures. The difficulty lies in determining a good set
of criteria that allows surgeons to accurately determine the patient population
requiring prophylactic fixation. Many different criteria have been suggested
including the size of the lesion; the type of cancer that metastasized
to bone; the location of the metastatic lesion; pain due to the lesion;
whether the lesion is lytic or blastic; irradiation of the lesion; and
the use of biomechanics to predict fracture.

However
researchers have disagreed on which are the important features to use
for diagnosis of imminent fractures as in most cases there has been evidence
published that supports and that refutes the use of each of the features
for diagnosis. When deciding which criteria to use, it is important to
consider both the accuracy with which it predicts an increased risk for
fracture and the convenience with which it can be measured. The biomechanical
factors that Hipp proposes to use seem as though they would be good predictors
of fracture, but Hipp did not provide an easy way to collect the data
required making them less useful as a diagnostic tool. While there is
evidence that the size of the lesion could be a good predictor for fracture,
the difficulty in accurately determining the size radiographically makes
it less useful diagnostically.

The
other variables discussed are much easier to determine in patients and
therefore would seem more useful diagnostically. However, based on the
research it seems that one criteria alone is not accurate enough to predict
and increased risk of fracture. Rather, having the requirement for fixation
involve the presence of several of these criteria would be better because
while each criteria individually is subject to error by the physician,
probability indicates that the chance of having false negatives and false
positives would decrease with the more factors involved. Therefore, this
writer feels that, while not ideal, the best diagnostic system to use
is the scoring system proposed by Mirels who requires the analysis of
4 criteria in determining risk of fracture. In addition, his research
indicates specific scores over which patients should have prophylactic
surgery.

Therefore,
surgeons would be able to relatively easily determine which of the criteria
their patient has, assign them a score, and decide whether to perform
surgery based on the score and clinical suspicion. While this system seems
to be the best for now, it is likely that with improvements in imaging
studies and further research, new criteria and modifications of old criteria
will soon be proposed. . Metastatic bone disease is the most common malignant
bone lesion seen in adults. Bone is the third most common site for metastases
after the lung and the liver (H,I). 7-27% of all cancer patients each
year are likely to have a metastatic bone defect (H). The incidence of
pathologic fractures in patients with malignant disease is 1-2% and 25%
of all metastases to long bones progress to fractures (U).